Synthesis of fluorosilyl compounds

Abstract

The disclosures herein relate to methods of synthesising a compound of formula (1):wherein PG, R2 and R3 are as defined herein, and the use of said methods in the manufacture of conjugates that bind to PSMA.

1 . A method of preparing a compound of formula (1) comprising reacting a compound of formula (2) with an alkyllithium reagent of formula (3) and a compound of formula (4): 
       
         
           
           
               
               
           
         
         wherein PG is a protecting group; 
         X is Br, Cl or l; 
         R 2  and R 3  are independently linear or branched C 1-10  alkyl; 
         R 1  is linear C 1-6  alkyl; and 
         wherein the alkyllithium reagent of formula (3) is added to a mixture comprising the compounds of formula (2) and (4). 
       
     
     
         2 . The method of  claim 1 , wherein the alkyllithium reagent is n-butyllithium. 
     
     
         3 . The method of  claim 1 or claim 2 , wherein PG is an acid-labile protecting group. 
     
     
         4 . The method of  claim 3 , wherein PG is tert-butyldimethylsilyl(TBDMS). 
     
     
         5 . The method of any one of  claims 1 to 4 , wherein X is Br. 
     
     
         6 . The method of any one  claims 1 to 5 , wherein R 2  and R 3  are both tert-butyl. 
     
     
         7 . The method of any one of  claims 1 to 6 , wherein the mixture comprising the compounds of formula (2) and (4) is maintained at a temperature of between −5° C. and 10° C. during addition of the alkyllithium reagent. 
     
     
         8 . The method of any one of  claims 1 to 7 , additionally comprising a step of deprotecting the compound of formula (1) using an acid to obtain a compound of formula (5): 
       
         
           
           
               
               
           
         
       
     
     
         9 . The method of  claim 8 , wherein the acid is hydrochloric acid. 
     
     
         10 . The method of  claim 8 or claim 9 , additionally comprising a step of oxidising the compound of formula (5) to obtain a compound of formula (6): 
       
         
           
           
               
               
           
         
       
     
     
         11 . The method of  claim 10 , wherein the oxidizing agent is potassium permanganate. 
     
     
         12 . The method of  claim 10 or claim 11 , further comprising a trituration purification step. 
     
     
         13 . The method of  claim 12 , wherein the compound of formula (6) is used in the manufacture of a radiopharmaceutical. 
     
     
         14 . The method of  claim 13 , wherein the radiopharmaceutical is a ligand-SIFA-chelator conjugate, comprising:
 (a) one or more ligands which are capable of binding to prostate-specific membrane antigen (PSMA);   (b) a silicon-fluoride acceptor (SIFA) moiety which comprises a covalent bond between a silicon and a fluorine atom; and   (c) one or more chelating groups, optionally containing a chelated nonradioactive or radioactive cation.   
     
     
         15 . The method of  claim 14 , further comprising an 18F fluorine exchange step. 
     
     
         16 . The method of  claim 14 or 15 , wherein the chelator comprises a chelated nonradioactive Ga 3+  cation. 
     
     
         17 . The method of any one of  claims 14 to 16 , wherein the ligand-SIFA-chelator conjugate is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         18 . A composition comprising a ligand-SIFA-chelator conjugate selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein said compound is prepared using the method of  claim 12 , and wherein said composition comprises no more than 0.1% (w/w) of a compound comprising a group of the formula: 
       
       
         
           
           
               
               
           
         
       
     
     
         19 . A composition according to  claim 18 , for use as a cancer diagnostic or imaging agent or in the treatment of cancer. 
     
     
         20 . A composition according to  claim 18 , for the diagnosis, imaging or prevention of neoangiogenesis/angiogenesis. 
     
     
         21 . A composition according to  claim 18 , for use as a cancer diagnostic or imaging agent or for use in the treatment of cancer wherein the cancer is prostate, breast, lung, colorectal or renal cell carcinoma.